A joint project of the Graduate School, Peabody College, and the Jean & Alexander Heard Library

Title page for ETD etd-07142015-181404

Type of Document Dissertation
Author Mrozowski, Roman Michal
Author's Email Address roman.m.mrozowski@gmail.com
URN etd-07142015-181404
Title Targeting the Ser/Thr protein kinase RSK to reduce breast cancer metastasis
Degree PhD
Department Pathology
Advisory Committee
Advisor Name Title
Alissa Weaver Committee Chair
Andries Zijlstra Committee Member
David Wasserman Committee Member
Deborah Lannigan Committee Member
Ian Macara Committee Member
Vito Quaranta Committee Member
  • kinase inhibitor
  • allosteric inhibitor
  • ribosomal S6 kinase
  • RSK
  • cancer metabolism
  • SL0101
Date of Defense 2015-05-15
Availability unrestricted
RSK is a family of four Ser/Thr protein kinases activated by ERK1/2 signaling. RSK is often misregulated in a variety of cancers, including breast and prostate. More recently, RSK1 and RSK2 have been shown to promote metastasis in vivo. Our laboratory has described the first potent and selective small molecule of RSK, SL0101. We found that this compound is not suitable for in vivo studies, therefore we set out to develop and validate new analogues based on the SL0101 pharmacophore. Here, we report a series of modifications improving the in vivo properties of SL0101. We characterize the mode of inhibition of RSK by SL0101. We find that this molecule acts as an allosteric non-competitive inhibitor of RSK. In addition, we discover that SL0101 is an isoform-selective inhibitor of RSK1/2 and not RSK3/4. The importance of these findings is highlighted by the fact that RSK1/2 serve tumor-promoting functions, while RSK3/4 are thought to be tumor suppressors. Therefore, SL0101 displays a desired isoform-selectivity as a potential novel therapeutic strategy to treat cancers.

Isoform-specific functions of RSK are not very well understood. Here, we describe development of a biotin labeling-mediated proteomic screen to identify novel RSK1 interacting partners. We find that RSK1 interacts with intracellular membranes, while RSK2 does not. We identify potential novel RSK1-binding partners among the proteins of the endoplasmic reticulum and mitochondrial membranes. Our results suggest that RSK1 may be involved in regulation of protein synthesis and energy homeostasis. In support of this hypothesis, we uncover a novel function of RSK1/2 in stimulating mitochondrial oxidative phosphorylation in breast cancer cells. We find that this function of RSK1/2 is specific to transformed cells. Therefore, we postulate that RSK1 can be involved in the metabolic transformation of breast cancer cells. Blocking this function by means of small molecules we develop could constitute a novel therapeutic strategy to target alterations in metabolism of cancer cells.

  Filename       Size       Approximate Download Time (Hours:Minutes:Seconds) 
 28.8 Modem   56K Modem   ISDN (64 Kb)   ISDN (128 Kb)   Higher-speed Access 
  dissertationRMrozowski.pdf 13.80 Mb 01:03:52 00:32:50 00:28:44 00:14:22 00:01:13

Browse All Available ETDs by ( Author | Department )

If you have more questions or technical problems, please Contact LITS.